Pharmaceutical formulation having enhanced bile acid binding affinity

Abstract

A pharmaceutical formulation comprising a polymeric resin having bile acid binding properties in combination with at least one bile acid binding material which enhances the bile acid binding affinity and/or capacity of the formulation, methods for preparing the formulations and methods for using the formulations.

We claim: 
     
       1. A pharmaceutical formulation comprises a polymeric resin having bile acid binding properties selected from the group consisting of cholestyramine and colestipol in combination with at least one entrapped bile binding material for enhancing the bile acid binding affinity and/or capacity of the formulation. 
     
     
       2. The formulation of claim 1 wherein the bile binding material is selected from the group consisting of carbohydrates which bind bile acids, lipids which bind bile acids, proteins and proteinaceous materials which bind bile acids, and antibodies and albumins which bind bile acids. 
     
     
       3. The formulation of claim 1 wherein the bile binding material is a carbohydrate or carbohydrate fragment having an affinity for bile acid. 
     
     
       4. The formulation of claim 3 wherein the carbohydrate is a cyclodextrin selected from α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin. 
     
     
       5. The formulation of claim 3 wherein the carbohydrate is a cyclodextrin derivative selected from the group consisting of β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 3-hydroxypropyl-β-cyclodextrin, 2,3-dihydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, and heptakis (2,6-di-O-methyl)-β-cyclodextrin. 
     
     
       6. The formulation of claim 1 wherein the bile binding material is present in an amount equal to from 10% to 50% by weight of the formulation. 
     
     
       7. A method for reducing cholesterol levels in a patient in need thereof which comprises administering to said patient an effective amount of a polymer resin capable of binding bile acids selected from the group consisting of cholestyramine and colestipol in combination with one or more entrapped bile binding material for reducing the cholesterol levels of the patient. 
     
     
       8. The method of claim 7 wherein the bile binding material is selected from the group consisting of carbohydrates which bind bile acids, lipids which bind bile acids, proteins and proteinaceous materials which bind bile acids, and antibodies and albumins which bind bile acids. 
     
     
       9. A process for preparing an improved pharmaceutical formulation by incorporating or diffusing at least one bile binding material into a polymeric resin capable of binding bile acids selected from the group consisting of cholestyramine and colestipol and subsequently retaining the bile binding material within the resin. 
     
     
       10. A process as set forth in claim 9 wherein the bile binding material is a binding carbohydrate, protein or lipid material or fragment or derivative thereof, said process being further defined as combining styrene, divinyl benzene, catalyst, and a cyclodextrin in water and forming an emulsion, heating the mixture to 85° C. until polymerization is complete, followed by swelling the resin in ether and reacting with chloromethyl ether at 0° C., then swelling in toluene and reacting with trimethylamine at 85° C. 
     
     
       11. The process of claim 9 wherein chloromethyl styrene and divinyl benzene are added in the presence of a catalyst to accelerate polymerization, adding water to form an emulsion, heating to 85° C. until polymerization is complete, followed by swelling the resin in toluene and reacting with trimethylamine. 
     
     
       12. The process of claim 10 wherein chloromethylated polystyrene is swelled in toluene, heated gradually, and reacted with trimethylamine. 
     
     
       13. The process of claim 10 wherein water is excluded from the formulation. 
     
     
       14. A process for preparing an improved pharmaceutical formulation by incorporating or diffusing at least one bile binding material into a polymeric resin capable of binding bile acids selected from the group consisting of cholestyramine and colestipol and subsequently retaining the bile binding material within the resin by the steps of swelling the resin in a solvent medium, mixing the resultant resin with the bile binding material and drying the mixture thereby shrinking the resin and entrapping therein the bile binding material. 
     
     
       15. The process of claim 14 wherein the alkali metal salt of an alkylbenzene-sulfonic acid is sodium dodecylbenzenesulfonate, the polyethylenepolyamine is diethylenetriamine and the cross-linking agent is epichlorohydrin. 
     
     
       16. The process of claim 14 wherein a second addition of a cross-linking agent is added following addition of the diethylenetriamine.